Multivalent feedback regulation of HMG CoA reductase, a control mechanism coordinating isoprenoid synthesis and cell growth.
Multivalent feedback regulation of HMG CoA reductase, a control mechanism coordinating isoprenoid synthesis and cell growth.
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发表时间：
1980-07
影响因子：
6.5
通讯作者：
M. Brown;J. Goldstein
中科院分区：
文献类型：
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作者：
M. Brown;J. Goldstein
紧缩素(ML-236B)是3-羟基-3-甲基戊二酰辅酶A还原酶的一种强有力的竞争性抑制剂，它的出现使得在培养的哺乳动物细胞中展示了甲氧戊酸代谢和类异戊二烯合成的一个迄今未被怀疑的方面。3-羟基-3-甲基戊二酰辅酶A还原酶是合成甲氧戊酸的酶，它似乎是通过多价反馈机制来调节的。完全抑制还原酶需要至少两种调节剂的存在：1)胆固醇，通常来自血浆低密度脂蛋白(LDL)；2)非甾醇产物，通常由甲氧戊酸内源合成。有证据表明，这两种还原酶调节因子对哺乳动物细胞在培养中的生长可能是必不可少的。3-羟基-3-甲基戊二酰辅酶A还原酶的多价反馈调节，以及甾醇合成途径中其他酶的次级调节变化，协调甲羟戊酸代谢的分支途径，以确保胆固醇和非甾醇产物的持续供应。这些新发现对于理解类异戊二烯代谢及其与细胞生长的关系具有重要意义。
The availability of compactin (ML-236B), a potent competitive inhibitor of 3-hydroxy-3-methylglutaryl Coenzyme A reductase, has permitted the demonstration of a hitherto unsuspected aspect of mevalonate metabolism and isoprenoid synthesis in cultured mammalian cells. 3-Hydroxy-3-methylglutaryl Coenzyme A reductase, the enzyme that synthesizes mevalonate, appears to be regulated through a multivalent feedback mechanism. Full suppression of the reductase requires the presence of at least two regulators: 1) cholesterol, which is normally derived exogenously from plasma low density lipoprotein (LDL), and 2) a nonsterol product, which is normally synthesized endogenously from mevalonate. Evidence indicates that both of these regulators of the reductase may be essential for the growth of mammalian cells in culture. The multivalent feedback regulation of 3-hydroxy-3-methylglutaryl Coenzyme A reductase, together with secondary regulatory changes in other enzymes of the sterol synthetic pathway, coordinates the branched pathway of mevalonate metabolism so as to assure a constant supply of cholesterol and nonsterol products. These new findings have important implications for the understanding of isoprenoid metabolism and its relation to cell growth.